In this specification where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not an admission that the document, act or item of knowledge or any combination thereof was at the priority date publicly available, known to the public, part of the common general knowledge or known to be relevant to an attempt to solve any problem with which this specification is concerned.
Improving the rate and extent of absorption of oral formulations of compounds has been the subject of substantial research. In general, once an immediate release solid swallow composition reaches the stomach, it undergoes disintegration and/or dissolution and passes into the small intestine where the active ingredient is absorbed across intestinal walls into the circulatory system via the portal vein and liver before reaching the site of action. For drugs where absorption is not rate limited, fast disintegration and fast dissolution of the active ingredient should promote fast absorption in vivo.
Solid dosage forms for oral administration can be categorized into three major groups. Those described as swallow formulations are intended to be swallowed whole. Those described as orally disintegrating or orally dissolving or chewable, are intended to be dispersed or dissolved in the mouth before swallowing. The third group is generally called dispersible or soluble formulations that are intended to be dissolved or dispersed in liquid before administration, such that the patient swallows the resultant solution or dispersion.
Of the group of swallow formulations, some are designed for sustained or delayed release through the use of coatings or other devices that control the site of release of the drug within the gastrointestinal tract. Examples include enteric coated tablets to avoid the local gastric toxicity which occurs with some acidic drugs such as the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and controlled or multiphase release of drugs to allow once daily dosage.
Other swallow formulations may be designed for immediate release providing fast dissolution of the active ingredient, with the aim of achieving fast absorption and fast onset of action.
This present invention relates to formulations manufactured as immediate release solid dosage forms intended to be swallowed intact, which will achieve fast dissolution with fast absorption of the active ingredient.
The use of sodium bicarbonate and other alkali metal carbonates has been described for a number of different purposes in pharmaceutical dosage forms containing a variety of different actives.
Soluble or Dispersible Effervescent Formulations
The use of sodium bicarbonate and other alkali metal carbonates, as the base component of an effervescent couple in dosage forms intended for dissolution or dispersion in water prior to administration, is widely recognised. Typically the resultant effervescent solutions or dispersions exhibit fast absorption of the drug contained therein.
Such formulations generally contain effervescent couples such as citric acid and sodium bicarbonate in large amounts. For example, U.S. Pat. No. 6,245,353 (Tritthart et al) describes a tablet containing cetirizine with an effervescent couple for disintegration in water prior to administration. A variety of effervescent formulations which are intended to be dispersed and/or dissolved prior to administration are disclosed for example in U.S. Pat. No. 4,704,269 (Korab et al), U.S. Pat. No. 4,309,408 (Pathak et al) and U.S. Pat. No. 4,942,039 (Duvall et al).
US Patent Application 20050147671 (Reiner at al) describes a fast absorbing formulation of diclofenac and one or more alkali metal carbonates or bicarbonates in small amounts. This disclosure predominantly relates to effervescent powder formulations added to water before administration.
U.S. Pat. No. 4,834,966 (Gazzaninga et al) describes granulates which are completely dissolved in water and administered as an aqueous solution which results in reduced time to reach peak plasma concentration. The granules containing arginine, ibuprofen and sodium bicarbonate reportedly provide enhanced dissolution of ibuprofen in water.
The purpose of the present invention is to incorporate the advantages of improved absorption and reproducibility of dispersible and/or soluble formulations into swallow formulations that are more convenient, and remain the preferred dosage form for many patients, particularly for regular use.
Disintegration
In swallow formulations, the use of bicarbonates has been described to act as a disintegrant through the production of gaseous carbon dioxide when the base reacts with acid.
U.S. Pat. No. 5,681,583 (Conte et al) uses agents such as sodium bicarbonate in one layer of a multi-layered controlled-release swallow tablet. The sodium bicarbonate effervesces in contact with acid solutions achieving fast disintegration and dissolution of the drug into water and the intestinal fluid.
U.S. Pat. No. 6,197,336 (Grassano et al) describes a swallow formulation containing a ternary mixture of ibuprofen with arginine and linear PVP which, when blended with other ingredients including 5-10% sodium bicarbonate (15-40 mg) with respect to ibuprofen, is readily compressible and achieves complete dissolution in pH 7.2 phosphate buffer in 10 minutes.
US Patent Application 20020034540 (Price et al) describes a compressed dosage form containing at least 35% by weight ibuprofen with sufficient alkali metal carbonate or bicarbonate in the range 5-15% of the tablet weight, such that the crushing strength of the tablet is 6.5-15 Kp and the disintegration time is less than 10 minutes. This discloses the use of alkali metal carbonates as a disintegrant in the range 25-75 mg per tablet.
These disclosures describe relatively low concentrations of alkali metal carbonates that will not increase the pH and hence will not increase the solubility of acidic drugs.
Taste Masking
A different application of bicarbonates is their use to improve the taste and palatability of orally dispersible or soluble dosage forms of some drugs.
This benefit of bicarbonates is noted by Reiner et al in US Patent Applications 20050147671 and 20050215643. They describe the use of relatively low levels of alkali metal bicarbonates, 20-80% by weight with respect to diclofenac (10-40 mg for a 50 mg dose), in various dosage forms including soluble or dispersible powders, two layered tablets and liquid drop solutions. The alkali metal bicarbonates improve the palatability of the powder formulations that are intended for mixing with water before ingestion. In vivo, such formulations achieve faster and more reproducible absorption with higher peak plasma concentrations than commercially available products.
The taste masking effect of sodium or potassium salts including bicarbonates has been described for non-effervescent soluble formulations of ibuprofen in U.S. Pat. No. 5,262,179 (Gregory et al).
Isotonicity
Some publications teach the inclusion of about 630 mg sodium bicarbonate in swallow tablets so as to provide isotonic conditions in the stomach which promote absorption of the drug.
U.S. Pat. No. 6,316,025 (Grattan) describes a swallow tablet of paracetamol, an unionized drug, containing 300 mg to 1000 mg of sodium bicarbonate per tablet with a paracetamol to sodium bicarbonate ratio of between 0.74 and 1. Grattan et al., Eur. J. Pharm. Biopharm 49(3): 225-229, 2000, subsequently reported that a formulation with 630 mg sodium bicarbonate provided improved pharmacokinetic outcomes. It was suggested that this was due to an osmotic effect of the level of sodium bicarbonate, which would be isotonic when two tablets are ingested with 100 mL of water and which would promote absorption. Kelly et al, Pharmaceutical Research, 2003, 20 (10) 1668-1673, attribute the faster absorption of paracetamol in vivo from a formulation containing 1260 mg sodium bicarbonate per dose, to faster disintegration and dissolution caused by the resultant effervescence, and the prokinetic effect of the resultant isotonic solution on gastric emptying.
Similarly, US Patent Application 20040204475 (Humphrey) teaches the use of sufficient sodium bicarbonate with eletriptan, a basic drug, to create an isotonic solution in the duodenum, with examples containing 630 mg per tablet.
Neutralising Gastric pH
U.S. Pat. No. 6,699,885 (Phillips) relates to formulations including omeprazole and bicarbonate or carbonate to protect the omeprazole from gastric acid degradation in amounts from about 250 mg to 4,000 mg, thus comprising the major proportion of the tablet by weight. This teaches the use of high levels of antacid to neutralise the gastric contents and so protect the drug from degradation. This eliminates the need for enteric coating which delays dissolution and absorption.
Dissolution Testing
Dissolution testing provides a convenient in vitro method to measure the dissolution of a formulation, which is one factor that can be used in predicting its in vivo dissolution. Fast in vitro dissolution under test conditions it typically indicative of fast in vivo dissolution. In turn, this typically favours the fastest possible absorption of the drug to the extent of the inherent absorption characteristics of that drug.
Further to this, the FDA Guidances for Industry based on the Biopharmaceutics Classification System (BCS) Guidance and in vitro dissolution testing assigns drugs to one of four classes depending on their solubility and intestinal permeability. For example, BCS Class 1 drugs with high solubility and high permeability, rapid in vitro dissolution correlates with fast in vivo dissolution and fast absorption. A point-to-point IVIVC is expected for poorly water soluble drugs where there is no intestinal permeability limitation (Class 2), but IVIVC is less likely for Class 3 and Class 4 drugs which are permeability limited.
Certain dissolution media can be used to assess the effect of different formulations in modifying gastric pH and the impact of this on drug dissolution.
Basic and Amphoteric Actives
It is widely accepted that raising the pH will reduce the solubility and hence inhibit the dissolution of basic compounds. Precipitation of the basic compound ondansetron in alkaline solutions containing sodium bicarbonate has been reported as a result of the effect of pH on the solubility of this basic drug (Jaronsinski P F and Hirschfield S, N. Eng. J. Med. 325:1315-1316, 1001).
Reduced solubility at high pH can prove advantageous for bitter tasting drugs. WO 2004/017976 (Tian et al) describes a fast dissolving and fast disintegrating, taste masked oral dosage form comprising the basic compound sildenafil. The specification describes the use of any pharmaceutically acceptable pH raising agent to inhibit dissolution of sildenafil, preventing dissolution of sildenafil in the mouth and thus masking the bitter taste of the drug. Agents that raise or increase the pH include sodium carbonate, sodium bicarbonate, calcium carbonate and magnesium carbonate.
US Patent Application 20050032867 (Baker et al) describes a fast disintegrating and dispersing sumatriptan formulation comprising about 5 to about 50% by weight base component. The base component of the formulation reacts with the acid component of the stomach, sumatriptan or acid component of the tablet to generate gas so as to facilitate the dissolution of the drug and hence its absorption. There is no teaching in relation to the effect of the base component on the solubility of the drug and its dissolution.
On the basis of these disclosures, it would be expected that the addition of bases such as carbonates to therapeutic compounds that are bases, salts of bases, amphoteric compounds or salts of amphoteric compounds, will reduce their solubility and hence dissolution as a result of the increased pH. Unexpectedly, we have found that for swallow formulations in the case of basic and amphoteric drugs, where increased pH is likely to lead to lower solubility and hence worse dissolution and absorption, the use of pH modulating agents can still achieve increased dissolution and potentially increased absorption. Furthermore, if a carbonate is used in a swallow formulation, with the level optimized for each drug, then enhanced dissolution can always be achieved, particularly for drugs with limited solubility.
Acids and Unionized Actives
A number of publications disclose the use of alkaline agents with acidic and unionized actives that differ from the present invention.
One example is reduced gastric toxicity of NSAIDs in swallow formulations which, unlike the present invention, contain cyclodextrins. U.S. Pat. No. 5,854,226 (Penkler et al) is directed to such formulations that minimize gastric irritation and achieve rapid absorption. These contain an inclusion complex of the NSAID with cyclodextrin and an alkali agent present in an amount capable of forming an alkaline diffusion layer around the composition in the gastrointestinal tract.
Another example is directed to the provision of small tablets (around 330 mg, including about 220 mg naproxen) which are easy to manufacture and rapidly absorbed. International patent application WO 2005/041938 (Gruber et al) relates to non-effervescent formulations, comprising 30 to 90 wt % sodium naproxen and 1 to 70 wt % auxiliary agent, comprising at least one basic auxiliary agent. Dissolution testing disclosed in the examples shows no greater than 50 wt % dissolution within 300 sec using 1000 mL of 0.1 N hydrochloric acid and paddle speed of 50 rpm (using the European Pharmacopeia method).
A further example described in U.S. Pat. No. 6,165,506 (Jain et al) is a fast dissolving naproxen formulation comprising nanoparticulate naproxen (less than 600 nm particle size) having adsorbed to it surface a surface modifying agent such as polyvinylpyrrolidone.
Both WO 2005/041938 and U.S. Pat. No. 6,165,506 teach manufacture of a small tablet having low levels of a base such as sodium bicarbonate, alone or with an organic acid to increase dissolution rate by the resultant effervescence. Furthermore both applications teach comparatively low levels of binders and disintegrants, which are essentially substituted by the base/acid. Neither contain sufficient base to increase pH in vivo.
In contrast to these preceding examples, a relatively large amount of prior art deals with the use of sodium bicarbonate and other pH modulating agents to affect the absorption of acidic drugs, particularly acidic NSAIDs and their salts. These relate to the higher solubility of acidic drugs at elevated pH.
Many acidic drugs have limited solubility in acidic solutions and so are frequently used as the more soluble salt form. This will potentially improve dissolution in vitro and in vivo. However U.S. Pat. No. 4,704,405 (O'Neill et al) describes the lack of improved absorption from formulations containing sodium sulindac relative to the less soluble sulindac. The inclusion of a base such as tromethamine or sodium bicarbonate in swallow formulations containing sodium sulindac was found to achieve improved bioavailability and onset of action compared with conventional tablets. The excess base was found to improve the absorption by neutralizing the gastric contents, solubilising the drug at this higher pH and delivering the solution to the duodenum for absorption. High levels of sodium bicarbonate are used in an amount between 0.8 g and 2.0 g to neutralize the gastric contents.
However, Neuvonen, P. J and Kivisto, K. T. (Clin. Pharmacokinet. 27 (2) 120-8, 1994.) reviewed the effects of various antacids, including high doses of sodium bicarbonate and magnesium hydroxide, on the absorption of different weakly acidic drugs. They noted that, although all antacids had a similar neutralising effect on gastric acid and so would increase the pH and hence the drug solubility, the effects on absorption were different depending on the drug and the antacid.
WO 9744023 (Reiner et al) deals with the use of sodium and potassium bicarbonate to enhance absorption of salts of diclofenac. They disclose the use of low levels of bicarbonate, 10-40 mg relative to a 50 mg dose of diclofenac which also masks the bitter taste of the drug since the low amount of bicarbonate used will not significantly increase the pH and the solubility of the drug remains low.
The above examples teach the use of high levels of antacids and bicarbonates to neutralize gastric contents resulting in improved absorption, particularly where the elevated pH improves the solubility of poorly soluble acidic drugs.
Surprisingly it has been found that for swallow formulations, the inclusion of alkali agents in the formulation at levels that will increase the pH of an acidic dissolution medium, is not always associated with fast dissolution or fast absorption. However if a bicarbonate is used in a swallow formulation, with the level optimized for each drug, then enhanced dissolution can always be achieved, particularly for drugs with limited solubility, whether the drug is an acid, a salt of an acid or an unionized compound. Furthermore, in vivo studies using paracetamol as a marker drug for gastric emptying have shown that the use of bicarbonates in swallow formulations results in faster absorption than the use of other alkali agents despite increased gastric pH.
The rate of dissolution is further enhanced as the particle size of the therapeutic agent is reduced and the surface area correspondingly increased.
For acidic drugs, improved dissolution can be demonstrated at lower pH values prior to total neutralization of the acid. This allows the use of levels of bicarbonates lower than those required to completely neutralize the gastric contents, which is of particular importance for patients who need to restrict their sodium intake.
In accordance with the present invention, therapeutic compositions intended for administration intact are defined in which the addition of bases to the therapeutic compounds enable enhanced in vitro dissolution of the therapeutic agent. In particular the present invention defines therapeutic compositions in which the addition of bases such as soluble carbonates or bicarbonates to therapeutic compounds chosen from the group comprising acids, bases, amphoterics, unionized actives, their salts, their proactive forms or combinations thereof will enable enhanced in vitro dissolution of the therapeutic agent.